M. Nooromid1, L. Xiong1, K. Wun1, T. Jiang1, E. Chen1, O. Eskandari1, K. J. Ho1 1Northwestern University,Surgery,Chicago, IL, USA
Introduction: The short chain fatty acids (SCFA) acetate, propionate and butyrate are produced primarily by the gut microbiome from metabolism of dietary fiber. SCFA serve as a source of energy but also act as signaling molecules. Our prior work in a rat model has demonstrated that butyrate potentially ameliorates neointimal hyperplasia development after arterial injury. To expand our understanding of how butyrate modulates neointimal hyperplasia, we utilized a mouse model of carotid artery ligation, dietary supplementation with butyrate, and knockout mice lacking free fatty acid 3 (FFAR3), a G protein-coupled receptor activated by butyrate.
Methods: 21-week-old male C57BL6 mice were given drinking water supplemented with butyrate (.5 mg/mL) or control water for four weeks prior to undergoing left carotid artery ligation. Serum butyrate concentration was assessed by gas chromatography. Four weeks later, mice were sacrificed and bilateral carotid arteries were harvested for morphometric analysis. A separate cohort FFAR3 knockout mice also underwent left carotid artery ligation and similar morphometric vessel analysis.
Results: Post-ligation common carotid arteries from butyrate-treated mice developed significantly less neointimal hyperplasia development than control-treated mice (neointima area .047 ± .008 mm2 control vs. .019 ± .005 mm2 butyrate; P=.03), which correlated inversely with changes in serum butyrate levels (2.3 ± .63 mg/mL control vs. 1.2 ± .12 mg/mL butyrate; P<.001). Interestingly, FFAR3 knockout mice demonstrated significantly decreased neointimal hyperplasia compared to wild-type mice (P=.03).
Conclusion: Butyrate has a protective effect on neointimal hyperplasia development after carotid ligation, but the role of FFAR3 on mediating this effect is unclear and likely complex. Future studies will focus on validating these findings in alternative murine models and exploring FFAR3 signaling in ex vivo studies.